Description:

This research proposal seeks to test the hypothesis that perinatal low level Methylmercury (MeHg) exposure results in 1) a decreased production of neurons and 2) the inhibition of migration of neurons during brain development. The experimental design will distinguish between three potential mechanisms responsible for migration deficits (inhibition of microtubule, and inhibition of neuron cell adhesion molecules).

Approach:

C57BL/6 mice will be exposed to low level MeHg (0.0, 0.05, 0.1, and 0.4 mg MeHg/kg body weight) via their drinking water. The females will be breed and their offspring will be sacrificed at key developmental points (GD14, PND 14, and PND 21) corresponding to important cell proliferation and/or cell migration phases of the brain. The right side of the brain will be examined with new unbiased stereology (neurons, astrocytes, microglia, and oligodendrocytes) in four brain regions (cerebral cortex, hippocampus, thalamus, and cerebellum). The left side of the brain will be used for determination of total mercury by cold vapour atomic absorption fluorescence. Additional brains will be devoted to quantification of changes in specific moieties (microtubules, NCAM, GSH cycle related enzymes, GSH levels, and indicators of apoptosis) by quantitative scanning laser cytometry.

Expected Results:

The research plan seeks to combine the results of the unbiased stereology estimates with scanning laser cytometer determination of changes in these specific moieties. This unique combination of methodologies will determine both the average cell and structure values of these moieties, allowing for an unprecedented sensitivity in quantification of effects of low level perinatal tissue. The expected results will allow for the distinction between the relative contribution each of the investigated mechanisms has on the observed change in cell number or migration deficit outcomes.

Improvement in Risk Assessment of Risk Management:

The expected results directly address areas of deficient scientific knowledge
related to low level perinatal MeHg exposure in the developing fetal brain as
outlined and identified by the EPA Mercury Study Report to Congress. V. Health
Effects of Mercury and Mercury Compounds (December, 1997). Improvements in the
scientific knowledge in the area will lead directly to a better understanding of
the risk facing humans relative to low level MeHg Exposure from the environment.
Furthermore, the paradigm of combining the new stereology methodologies with
quantitative laser cytometry, developed in this research project, will provide
unprecedented sensitivity of subtle structural changes in the CNS (as well as
other tissues). This paradigm will serve as a model for other investigator
initiated research projects in which subtle, but important effects are expected.
Ultimately this sensitivity will lead to improved assessment and modeling of low level effects of a wide variety of environmental toxicants.

Progress and Final Reports:

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.